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MB Martin, SV Angeloni, P Garcia-Morales, PF Sholler, MD Castro-Galache, JA Ferragut, and M Saceda

Results presented in this study demonstrate that treatment of MCF-7 cells with taxol resulted in induction of estrogen receptor-alpha (ER alpha) gene transcription with a subsequent increase in ER alpha mRNA; this effect was promoter specific since taxol did not affect total transcription in MCF-7 cells and lacked an effect on transcription of the human acidic ribosomal phosphoprotein protein PO, progesterone receptor, and pS2 genes. In contrast to the increase in transcription of the ER alpha gene, taxol inhibited translation of the ER alpha mRNA. This effect is also transcript specific since taxol did not alter total protein synthesis and did not affect the concentration of progesterone receptor protein in the cell. The overall result of taxol treatment was to decrease the concentration of ER alpha protein in the MCF-7 cells. Evidence is presented that the effects of taxol on ER alpha gene transcription may be mediated through the induction of p53.

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SV Angeloni, MB Martin, P Garcia-Morales, MD Castro-Galache, JA Ferragut, and M Saceda

The results presented here demonstrate that p53 upregulates estrogen receptor-alpha (ER alpha) expression in the human breast cancer cell line MCF-7. Two approaches were used to alter the activity of p53 in the cells. In the first approach, stable transfectants expressing an antisense p53 were established. In the stable clones, expression of antisense p53 resulted in a decrease in the expression of ER alpha protein. In the second approach, MCF-7 cells were transiently transfected with wild-type p53. Overexpression of p53 increased the amount of ER alpha. To determine whether the effects of p53 on the expression of ER alpha were due to changes in transcription, deletion mutants of the ER alpha promoter were used. This experimental approach demonstrated that p53 up-regulates ER alpha gene expression by increasing transcription of the gene through elements located upstream of promoter A. Transfection assays using p53 mutants further demonstrated that the p53-induced increase in ER alpha gene transcription was not dependent on the ability of p53 to bind to DNA but on its ability to interact with other proteins.